Background: Neuromyelitis optica spectrum disorders (NMOSD) is an inflammatory and heterogeneous astrocyte disorder of the central nervous system (CNS), concerned because of its high pathogenicity, high risk of recurrence, and poor prognosis. Optic neuritis (ON) is the first manifestation in 30% to 50% of NMOSD patients, and eventually involved optic nerve in 70% of patients. The idiopathic ON associated with NMO is called NMO-associated ON(NMO-ON). There are substantial costs to the countries and individuals associated with treatment of NMO-ON. Intravenous corticosteroids (IVCSs), as the first-line therapy, leads to unsatisfactory outcomes for NMO-ON and is associated with potential adverse events (AEs). Emerging evidences have proved the important value and potential prospect of plasma exchange (PLEX) in NMO-ON. Although PLEX is increasingly used in NMO-ON, its therapeutic effect and safety are still controversial. There are no systematic reviews yet that evaluated the effects of PLEX against other therapies in patients with NMO-NO. It is therefore timely to perform a systematic review to assess the efficacy and safety of PLEX on current research for its potential use in clinical practice in treating NMO-ON. Methods: The systematic review will include all of the randomized controlled trials (RCT) on the efficacy and safety of PLEX for NMO-ON. A relevant literature search by sensitive search strategies was conducted using the following electronic databases from their inception to November 30, 2019: PubMed, Web of Science, EMBASE, the Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang Database, China Science and Technology Journal database (VIP) and CBM. We will also search registers of clinical trials, potential gray literature, and conference abstracts. There are no limits on language and publication status. The literature screening, data extraction, and quality assessment will be conducted by 2 reviewers independently. The reporting quality and risk of bias will be assessed by other 2 researchers. Best-corrected visual acuity (BCVA), annualized relapse rate (ARR), the frequency and extent of adverse events (AEs) will be evaluated as the primary outcome. The secondary outcomes will include expanded disability status scales (EDSS), relapse-free rate, peri-papillary retinal nerve fibers layer (pRNFL) or macular volume, visual electrophysiology examinations, standard automated perimetry examinations, time to the next attack. Meta-analysis will be performed using RevMan5.3 software provided by the Cochrane Collaboration and Stata 12.0. Results: This study will provide a comprehensive review based on current evidence of PLEX treatment for NMO-ON in several aspects, including BCVA, ARR, the frequency and extent of adverse events (AEs), EDSS, relapse-free rate, etc. Conclusion: The conclusion of this study will provide evidence to determine whether PLEX is an effective and safe intervention for patients with NMO-ON. Ethics and dissemination: It is not necessary to obtain ethical approval for this study, given that this protocol is for a systematic review. The systematic review will be published in a peer-reviewed journal, presented at conferences and will be shared on social media platforms. PROSPERO registration number: PROSPERO CRD 42020162585.